Process of preparing 4-arylmethyl-quinolines



PROCESS OF PREPARING ,4-ARYLMETHYL- QUINOLINES Alexandei-R. Surrey,Albany, and Royal A. Cutler, West Sand Lake, N. Y., assignors toSterling Drug Inc, New York, N. Y., a corporation or Delaware NoDrawing. Application July 1, 1955 Serial No. 519,675

1 Claim. (Cl. 260-283) This invention relates to a novel process ofpreparin g 4 -arylmethylquinolines and to a particular group of '4-arylmethylquinolines prepared thereby.

This invention is a continuation-in-part of our copend- U ted StatesPate t ably taking place in two steps, namely: the hydrolysis of thenitrile group to a carboxyl group, and the elimination of carbon dioxidefrom the resulting alpha-aryl-alpha-(4- quinolyl)acetic acid.

The intermediate alpha-aryl-alpha-(4-quinolyl)acetonitriles aredisclosed and claimed in our U. 8. Patent 2,519,411,- issued August 22,1950. The aryl radical of these nitriles, designated as A, is preferablya monocyclic aryl radical of the benzene series. Thus, the aryl radicalcan be the unsubstituted phenyl radical or phenyl radicals substitutedby from one to three substitu'ents, such substituents includinghydroxyl; alkoxyl such as methoxyl,

ethoXyl, etc; dialkylamino such as dimethylamino; halogen, such aschloro, bromo, or iodo; lower alkyl such as methyl, ethyl, butyl, etc.;nitro; and other groups which the chemist appreciates will beunaffectedby the reaction conditions used in the preparation of theintermediate nitriles and in the process of our instant invention.Furthermor'e, said substituents can be in any of the available positionsof the phenyl nucleus, and where more than one, can be the same ordilferent and can be in any of the various position combinationsrelative to each other. The 4-quinolyl radical, designated as Q, as usedin the specification and in the appended process claims in generic andincludes the unsubstituted 4-quinolyl radical and 4-quinolyl radicalswherein the quinoline nucleus may be substituted by one or more,preferably one to three, of such substituents as: halo, includingchloro, broino, iodo and fluoro'; lower alkyl, including methyl, ethyl,propyl, amyl, and the like; hydroxy; lower alkoxy, including methoxy,ethoxy, propoxy, and the like; aryloxy, such as phe'noxy; aralkoxy, suchas benzyloxy; trihaloalkyl, such as trifluoromethyl; nitro; amino;substituted-amino, such as acetylarnino, ethylainino, diinethylamino,benzylamino, and the like; and other substituents. Furthermore, saidquinoline substituents can be in any of the available positions of thequinoline nucleus, and where more than one, can be the same or diiferentand can be in any of the various position combinations relative to eachother.

Our process, provides a means of obtaining excellent yields of said4-arylmethylquinolines (ACH Q). The

2,838,514 Patented June 10, 1958 2 process can be carried out undervarious conditions: e. g., by refluxing the appropriatealpha-aryl-alpha-(4- quinolyl)acetonitrile with about 60% aqueoussulfuric acid for about one hour; or by refluxing the nitrile withconcentrated sulfuric acid in ethanol for about twentytwo hours; or byrefluxing the nitrile in absolute ethanol for about eight hours whilepassing dry hydrogen chloride through the solution. Essentially, ourprocess involves heating an alpha-aryl-alpha-( l-quinolyl)acetonitrilein an acidic medium. In general, it is preferred to heat the nitrile atabout l50 C. with an excess over the stoichiometric amount of. a strongmineral acid, and optionally, in the presence of an inert diluent suchas water, a lower alkanol, a hydrocarbon, ,a 'halohydrocarbon, or alower fatty acid. As a specific illustration of our process, heatingalpha-pheny1-alpha-(4-quinolyl)acetonitrile in an acidic medium resultsin a quantitative yield of 4-benzylqu'inoline. This compound, 4-bnzylquinoline, has. been reported in the literature, however, the methods ofpreparing it have been far from being satisfactory. It was firstprepared by Rabe andPasternack [Ben 46, 1029 (1913)], who isolated it'asa by product from the action of benzylmagnesium chloride on4-cyanoquinoline. Bergman and Rosenthal [J prakt. Chem. 135,275 (19.32)]obtainedit in small yield from the action of benzylmagnesium chloride onquinoline, 2'- benzylquinoline being the main product. In addition,Bergstrom .[J. Org. Chem. '11, 55 (1946)] reported its preparation in37% yield by the action of chlorobenzene on lepidime the presence 'ofpotassium amide in liquid ammonia. Now, by our above-described method,it is possible to obtain this compound, as well as other l-arylmethylquinolines, in excellent yields.

Our inventionalso comprehends a particular group of4-arylmethylquinolines bearing halogen atoms in the benzene portion ofthe quinoline nucleus. These compounds have the general formula where Ais defined as above, R is hydrogen, methyl, halogen or nitro, X-is ahalogen atom and n is 1 to 2, inclusive. X comprehends chloro, bromo,iodo and fiuoro. These 4-arylmethyl-halogenated-quinolines have usefulparasiticidal properties, such as fungicidal activity. Illustrative ofthese compounds are the following: 4-(3,4dichlorobenzyD-7,8-dichloroquinoline;3-methyl-4-(3,4-dimethoxybenzyD-8-iodoquinoline;4-benzyl-7-chloroquinoline; 4-(4-chlorobenzyl-7 fluoroquinoline;3-nitro-4-benzyl-S,7-dichloroquinoline; 4-benzyl-3,7-d-ichloroquinoline;3-methyl-4-benzyl-6-bromoquinoline; 4-benzyl-6,8-dichloroquinoline;3-iodo-4-(3,4-dibromobenzyl)-5-chloroquinoline; and the like.

Also encompassed within the scope of our invention are4-arylmethyl-halogenated-quinolines in the form of their acid additionsalts with non-toxic inorganic or organic acids, such as hydrochloricacid, sulfuric acid, phosphoric acid, 'hydrobromic acid, hydroiodicacid, sulfamic acid, tartaric acid, citric acid, benzoic acid, and thelike.

The following examples will further illustrate specific embodiments ofour invention.

4-arylmethylquinolines These 4-substituted-quinolines were prepared byheating the related alpha-aryl-alpha-(4-quinolyl)acetonitriles 3 thefollowing procedures: Five parts by weight of an alpha-aryl-alpha-4-quinolyl) acetonitrile.

. and eight parts by volume each of concentrated sulfuric acid and waterwere refluxed vigorously for one hour.

Initially, carbon. dioxide evolves in copious amounts.

At the end of the heating period, the yellow solution was poured into amixture of ice and excess ammonium hydroxide.v The product whichseparated was taken up in a solvent such as ether, the extract driedover anhydrous calcium sulfate, and the solvent distilled to give aquantitative yield of pale yellow oil which solidified on standing.Recrystallization from petroleum ether gave the purified crystalline4-arylmethylquinoline.

In another preparation a solution of 5 g. ofalphaphenyl-alpha-(7-chloro-4-quinolyl)acetonitrile, 8 ml. ofconcentrated sulfuric acid, 2 ml. of water, and ml. of methanol wasrefluxed for 22 hours on a steam bath. Working up of the reactionmixture as described in the preceding paragraph yielded a quantitativeyield of the crude 7-chloro-4benzylquinoline, which when recrystallizedfrom petroleum'ether, melts at 93.594 C.

Another means of preparing said 4-arylmethylquinolines of the formulaACH Q is illustrated by the following preparation of7-chloro-4-benzylquinoline: Hydrogen chloride was passed for eight hoursinto a refluxing solution of 5 g. ofalpha-phenyl-alpha-(7-chloro-4-quinolyl) acetonitn'le dissolved in 50ml. of absolute ethanol. The solution was filtered while hot to removethe ammonium chloride which had separated, the filtrate cooled, ml. ofether added, and after standing two days the white solid which separatedwas filtered. The product obtained was 4 g. of impure7-chloro-4-benzylquinoline hydrochloride, M. P. 218-220 C. (withdecomposition), the structure of which was confirmed by converting intothe corresponding 7-chloro-4-benzylquinoline, which has propertiesidentical with the compound the preparation of which was described inthe above paragraph.

Other 4-benzylquinolines prepared according to the above procedures fromthe related alpha-phenyl-alpha- (4-quinolyD-acetonitrile include:4-benzylquinoline, M. P. 52 52.5 C. and mono-sulfate salt thereof, M. P.195 196 (3.; 5-chloro-4-benzylquinoline, M. P. 48.6-49.2 C. (corr.).

Using other alpha-aryl-alpha-(4 quinolyl)acetonitriles in the aboveprocedures the following 4-arylmethylquinolines can be obtained:4-(3,4-dichlorobenzyl)-7,8-dichloroquinoline;4-(4-chlorobenzyD-6,8-dichloroquinoline; 3-methyl-4-(3,4-dimethoxybenzyl)-8-iodoquinoline; zyl-7-brornoquinoline;4-(4-chlorobenzyl)-7-fluoroquinoline;3-nitro-4-benzyl-5,7-dichloroquinoline; 3-nitro-4-(3,4-dichlorobenzyl)quinoline; 4-benzyl-3,7-dichloroquinoline;6-methoxy-4-(4-methoxybenzyl)-quinoline; 3-methyl-4-benZyl-6-bromoquinoline; 4-benzyl-6,8-dichloroquinoline;3-iodo-4-(3,4-dibromobenzyl)-5-chloroquinoline; and the like.

The structure of our 4-arylmethyl-halogenated-quinolines follows fromthe mode of preparation, that is, by heating the correspondinalpha-aryl-alpha-(halogenated- 4-quinolyl)acetonitriles to completelyremove the CN group, and from the fact that similarly heatingalphaphenyl-alpha-(4-quinolyl)acetonitrile yields the known 4-benzylquinoline shown above.

Our 4-arylmethyl-halogenated-quinolines were found to have fungicidaland fuugistatic activity when tested against various fungi, for example,Trichophyton inter digitale, Trichophyton mentagrophytes, andTrichophyton gypseum; these are fungal organisms which cause dermabydilution with maltose peptone broth.

4' tomycoses or mold infections of human and animal skin, or, as theyare commonly called, ringworm infections, such as ringworm of the foot(athletes foot), tinea sycosis in the horse, cow, dog, and sometimes inman. This antifungal activity was determined according to the followingprocedure: Spore suspensions were prepared from 15 day old cultures of'the test organism grown in maltose peptone broth. The mats were shakenwith glass beads, the resulting suspensions diluted and filtered througha 200 mesh Monel metal screen. This filtered spore suspension was thendiluted 1 to 10 with maltose peptone broth and 1 cc. of this dilutionadded to inoculate each of the culture tubes used in the test. Anaqueousethanolic stock solution was prepared by dissolving the compoundto be tested in N/LHCl, diluting with aqueousethanol (about 15 to 50%ethanol), and then adding water to produce a solution containing 0.5 mg.per ml. of the compound to be tested; the pH of this solution was thenadjusted to about 5.6 to 6.3 with N/LNaOH. Working dilutions of thecompound being tested were then prepared from this aqueous-alcohol stocksolution Inoculated-tubes of medicated medium were incubated for 10 daysat 25 C. to determine the fungistatic end-points, that is, the maximumeffective dilution to stop fungal growth. All tubes showing no growthafter 10 days were subcultured (0.1 cc. to 10 cc.) in maltose peptonebroth and incubated at 25 C. for an additional 10 days to determine thefungicidal end-points, that is, the maximum efiective dilution to killthe fungus. Illustrative of the anti-fungal activity of our compoundswhen tested according to the above-described procedure are theactivities of the 5- chloro-4-benzylquinoline and7-chloro-4-benzylquinoline as presented in the following table.

a Stock solution contained about 7% ethanol and had a pH of 5.65. bStock solution contained about 35% ethanol and had a pH of 6.25. Our4-arylmethyl-halogenated-quinolines are preferably administeredtopically; and they can be compounded with conventional excipients andadministered in the form of a powder, a liquid, a salve, an ointment, anaerosol, or any other convenient vehicular form suitable foradministering anti-fungal agents. Our quinolines can be formulated inthese various vehicular forms in dilutions of about 1:1000 to about120,000.

We claim:

A process for the preparation of a 4-arylmethylquinoline having theformula ACH Q, where A is a monooyclic radical of the benzene series andQ is a 4-quinolyl radical, which comprises heating analpha-aryl-alpha-(4- quinolyl)acetonitrile having the formula ACH(Q)CNin an acidic medium.

References Cited in the file of this patent UNITED STATES PATENTS2,568,778 Surrey et al Sept. 25, 1951 UNITED STATES PATENT OFFICECERTIFICATE OF CORRECTION Patent No. 2,838,514 June 10, 1958 AlexanderR; Surrey et al,

It is hereby certified that error appears in the above numbered patientrequiring correction and that the said Letters Patent should read ascorrected belowa Column 1, line 54, for in geread u is e column 2, line53, for "4-(4chlorob'enzyl-7-" read 4-(4-chlorobhzyl)-7- a Signed andsealed this 19th day of August 1958.a

(SEAL) At'fiest: if

KARL Ho AXLINE ROBERT C. WATSON Attesting Officer Comnissioner ofPatents

